The interaction between host platelets and circulating tumor cells is thought to facilitate hematogenous metastasis by an unknown mechanism. We have proposed that prostacyclin (PGI2), a natural product of the vessel wall and the most potent platelet antiaggregatory agent known, may function as an endogenous antimetastatic agent. Previously, we demonstrated that PGI2 inhibits platelet-enhanced tumor cell adhesion to plastic plates, type IV collagen, and endothelial cells, and significantly inhibits metastasis in vivo. Recent work from our laboratory demonstrated that PGI2 inhibits tumor-cell-induced platelet aggregation in a dose-dependent manner, as well as platelet alpha and dense granule release. We tested for possible synergism between PGI2 and other compounds known to effect platelet aggregation. These compounds include thromboxane synthase inhibitors, phosphodiesterase inhibitors, and calcium channel blockers. All of these compounds, as well as PGI2, are thought to effect platelet aggregation by affecting intraplatelet levels of free Ca2+. We observed that agents from all three groups tested combine in a synergistic manner with PGI2 to significantly inhibit tumor-cell-induced platelet aggregation at concentrations which, by themselves, had little or no inhibitory effect on platelet aggregation. Additionally, we determined that the probable mechanism through which nafazatrom, a antimetastatic compound, exerts its effects. Nafazatrom was found to be a reducing substrate for the peroxidase activity of prostaglandin H synthase. In ram seminal vesicle preparations, nafazatrom induced an elevation in levels of 6-keto-PGF1-alpha, the non-enzymatic hydrolysis product of PGI2. We are currently screening compounds for actions similar to that of nafazatrom and have found one that is a good reducing substrate for prostaglandin H synthase and is an effective antimetastatic agent in vivo. Our future research will be directed toward identifying compounds for their ability to increase PGI2 levels in vitro and in vivo. Inhibition of metastasis will be examined in vivo using PGI2 and PGI2-stimulating compounds in concert with other classes of platelet antiaggregatory agents. (L)